Neuroblastoma is the most common extracranial solid tumor of childhood. The majority of patients over one year of age develop locally aggressive and/or metastatic disease that is rapidly progressive. Retinoids, naturally occurring and synthetic analogues of vitamin A, can improve the outcome in children with high risk neuroblastoma The current practice of administering retinoids only after completion of cytotoxic chemotherapy is empiric, and studies on how best to integrate retinoids with cytotoxic chemotherapy for the treatment of neuroblastoma have not been performed. The objective of this proposal is to determine the optimal sequence of administration of retinoids when combined with cytotoxic drugs for the treatment of neuroblastoma. Neuroblastoma cell lines with characteristics representative of the diverse spectrum of neuroblastoma observed clinically will be studied in an in vitro and in vivo model. Retinoids with differing receptor-binding profiles will be studied to determine if synergistic or antagonistic interactions are receptor specific and to define which retinoid is the most potent enhancer of chemotherapy induced cytotoxicity. The interaction of retinoids with novel agents being developed for the treatment of neuroblastoma (see Projects 1, 2 and 3) will also be studied. Our specific aims are: Specific Aim 1. To determine whether retinoids with differing receptor specificity act synergistically in a sequence-dependent manner with cytotoxic agents in neuroblastoma cell lines. Hypothesis: Concomitant administration of retinoids with cytotoxic agents is superior to only administering retinoids following cytotoxic chemotherapy. Specific Aim # 2. Using targeted retinoid exposures based on human pharmacokinetic data, to determine whether observations made with drug combinations in vitro are relevant in an in vivo neuroblastoma model. Hypothesis: Due to differences between in vitro and in vivo drug exposure, only selected combinations of retinoid-cytotoxic drugs that are synergistic in vitro will prove to be synergistic in vivo. Specific Aim # 3. To determine the extent of isomerization between retinoic acid isomers and quantitate the intracellular concentrations of the geometric isomers associated with the observed endpoints. Hypothesis: lsomerization to retinoic acid isomers capable of binding the nuclear retinoic acid receptor (RAR) underlies the activity observed in model systems utilizing 13cRA.